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81 Cards in this Set
- Front
- Back
What does NSAIDS treat?
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headache, mild-mod arthritic pain
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what does Anticonvulsants, Tricyclic antidepressants, Serotonin/norepinephrine re-uptake inhibitors treat?
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Neurogenic pain
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What do opioids treat?
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Severe, chronic, malignant pain
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What kind of compounds are opioids? What kind of effects do they have?
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natural (opium poppy) or synthetic compounds that produce morphine-like effects
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What 4 diverse functions Opioid Analgesics treat?
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Sensory component (inhibiting response to pain stimuli)
Modulation of GI, endocrine and autonomic functions Emotional component (powerful rewarding and addicting properties) Cognitive component (learning and memory) |
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What are the 3 families of classical opioid peptides?
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Enkephalins(Pro-enkephalin)
Endorphins (POMC)(pre-opiomelanocortin) Dynorphins (Pro-dynorphin) |
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What is the common NH2 terminal “opioid motif” sequence?
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TYR-GLY-GLY-PHE-(MET or LEU)
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how many ligands and major receptors are there in Endogenous opioid system?
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>12 ligands (Table 21-1); 3 major receptor types
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What may be a critical functional variable in opioids?
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Duration of action of endogenous ligands may be a critical functional variable
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what is more important than activation of single receptor may be important?
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Pattern or profile of activation of multiple receptors by a ligand
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Intracellular trafficking of the receptors may vary as a function of what?
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receptor and the ligand
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Opioid Receptors are what kind of receptors? What do they inhibit? What chanels are they involved in?
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1)G-Protein coupled receptors
2)Inhibit adenylyl cyclase 3)Associated with ion channels |
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Opioid receptors increase what efflux and and decreasewhat influx? What does this impede?What is released?
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↑ post-synaptic K+ efflux (hyper-polarization) or ↓ pre-synaptic Ca2+ influx → impedes neuronal firing and transmitter release
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How do opioid receptors signal?
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May also signal via MAP kinase and Phospholipase C signaling pathways
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what does Chronic opioid exposure result in?
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myriad signaling adaptations that may be important in tolerance, sensitization and withdrawal symptoms
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What are the three opioid receptor families?
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(Mu)
(Kappa) (Delta) |
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Enkephalins interact more selectively with what receptors?
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receptors in periphery
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Analgesic properties of opioids mediated via which receptor?
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MU and K receptors in the dorsal horn
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What is the MOA of the mu-opioid Receptor agonists?
On the pre-synaptic neuron and the post synaptic neuron |
Activation of the opioid receptor ↓ Ca2+ influx in response to incoming action potential. This decreases release of excitatory neurotransmitters such as glutamate.
Activation of the opioid receptor ↑ K+ efflux and decreases the response of the post-synaptic neuron to excitatory neurotransmitters such as glutamate |
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Transient opioid administration can result in what? What kind of time frame can it occur in?
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acute tolerance.
Can occur w/in hours |
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Sustained opioid administration can result in what? How long does it take?
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classical tolerance (following days-weeks of treatment)
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What two things play a role in development of tolerance?
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Acute receptor desensitization and down-regulation likely
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How does Phosphorylation of μ and δ receptors occur?
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PKC, PKA and/or βARK
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What receptors can opioid receptors can undergo rapid agonist-mediated internalization via classical endocytic pathway?
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μ and δ but not κ
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Different ligands induce different what? What does this lead to?
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Different ligands induce different conformational changes in the receptors leading to divergent signaling pathways.
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In the brain stem, what do opioid receptors influence?
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respiration, cough, nausea and vomiting, blood pressure, pupillary diameter (miosis), control of gastric secretion)
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In the medial thalamus, what do opioid receptors mediate?
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mediates deep pain that is poorly localized and emotionally influenced
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In the Spinal cord, what receptors are involved? What are they involved in? What does it lead to?
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receptors in the substantia gelatinosa are involved with the receipt and integration of incoming sensory information, leading to the attenuation of painful afferent stimuli
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What do opioid receptors in the hypothalamus affect?
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affect neuroendocrine secretion
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Where are the the greatest concentration of opiate receptors in the limbic system located? What do they influence?
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Ithe amygdala. Influence emotional behavior.
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In the Periphery what do opioids also bind to? What do they inhibit the release of?
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sensory nerve fibers and their terms. Inhibit Ca2+ dependent release of excitatory proinflammatory substances (e.g. substance P) from these nerve endings.
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Morphine and clinically used opioid agonists exert what? What do they affect and what do they alter?
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Exert clinical and adverse effects via μ opioid receptors
Affect mood and rewarding behavior (euphoria) Alter respiratory, cardiovascular, GI and neuroendocrine function |
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Δ opioid receptor agonists are potent what?
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analgesics in animal models
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What do K receptors produce? What kind of effects do they produce?
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agonists produce analgesia mediated primarily at spinal sites (animal models)
Produce dysphoria and psychotic effects |
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What are strong agonist opioid analgesics? What are moderate agonists?
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Alfentanil, Fentanyl, Heroin, Meperidine, Methadone ,Morphine, Oxycodone, Remifentanil, Sufentanil
Codeine, Propoxyphene |
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analgesia of morphine and related opioid agonists occurs without what?
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Pain relief occurs w/o loss in consciousness
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Analgesia of morphine and related opioid agonists raises pain threshold at what level?
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at the level of the spinal cord and alter brain’s perception of pain.
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When therapeutic Rx of morphine and related opioid agonistsis given to normal, pain-free individual what happens?
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→ unpleasant experience
Nausea, vomiting, drowsiness, difficulty in mentation, apathy. With ↑ dose, toxic effects including respiratory depression may become pronounced. |
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Neural systems that mediate opioid reinforcement are distinct from those involved in what?
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involved in physical dependence and analgesia
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What is involved in involved in drug-induced reward? what does the data show?
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Dopaminergic pathways, particularly involving the nucleus accumbens,
Data show interaction between opioids and dopamine in mediating opioid-induced reward. |
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Morphine and related agonists cause what? how is this done? Where does this occur?
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respiratory depression by ↓sensitivity of brainstem respiratory center neurons to CO2.
Occurs at therapeutic Rx and is dose-dependent. |
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What is the most common cause of death w/acute opioid overdose?
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Respiratory depression
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In Miosis Pinpoint pupil results from what?
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stimulating μ and κ receptors
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In Miosis, what does morphine excite?
What does this result in the increase of? |
excites the Edinger-Westphal nucleus of the oculomotor nerve → ↑ parasympathetic stimulation to the eye
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morphine and related opioid agonists have what kind of effect in Depression of cough reflex?
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direct effect on a cough center in the medulla
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morphine and related opioid agonists have what kind stimulation during Emesis? What does it cause?
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direct stimulation of the chemoreceptor trigger zone in the area postrema of the medulla that causes vomiting.
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morphine and related opioid agonists decrease and increase what in GI tract? What does this result in?
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μ agonists ↓ acid secretion in stomach, ↓ gastric motility, ↓ motility and ↑ tone of SI circular smooth muscle. Results in constipation w/little tolerance. Can also increase biliary tract pressure due to contraction of gallbladder and constriction of biliary sphincter.
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morphine and related opioid agonists have what kind of cardiovascular affect? What does respiratory depression?
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morphine causes hypotension and bradycardia.
Respiratory depression results in dilation of cerebral vessels and ↑ CSF pressure |
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What does morphine stimulate? Contradicted in what patients?
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morphine stimulates histamine release form mast cells.
Asthmatics |
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morphine and related opioid agonists have what kind of effects in the endocrine?
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many effects including ↓ GNRH, corticotrophin releasing hormone, LH, FSH, adrenocorticotropic hormone, β-endorphin, testosterone and cortisol. ↑ GH, prolactin and antidiuretic hormone (urinary retention)
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What can morphine prolong? How?
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morphine may prolong 2nd stage of labor by transiently decreasing the strength, duration and frequency of uterine contractions
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How does Morphine help treat diarrhea?
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↓ motility and ↑tone of intestinal smooth muscle (can cause constipation)
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How does morphine help with acute pulmonary edema?
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IV morphine dramatically relieves dyspnea caused by pulmonary edema associated w/left ventricular failure presumably via vasodilation
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Absorption of morphine from the GI tract is____? What kind of metabolism does it go through? What kind of dosing is there?
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Absorption from GI tract is erratic; high first pass hepatic metabolism → IV, sc or IM dosing optimal
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Mepiridine is agonist to what receptors? What does it tx?
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Agonist to μ and κ.
Rx for acute, severe pain |
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Methadone is what kind of opioid? What is its potency compared to Morphine? Induces less what? Has a longer what?
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synthetic, orally active opioid (μ agonist) equal in potency (analgesia) to morphine but induces less euphoria and has longer duration of action.
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Fentanyl: chemically related to what? Describe its potency compared to morphine? What is it used as?
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related to meperidine, 100X more potent than morphine (analgesia) and is used in anesthesia.
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Describe fentayl lipophilicy? What kind of onset does it have? What kind of duration on action does it have?How is fentanyl administered?
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Highly lipophilic; rapid onset and short duration of action (15-30 min)
IV, epidural, intrathecal injection |
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When is an example that fentayl is used?
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Cardiac surgery → minimal effect on myocardial contractility
Oral transmucosal (cancer patients w/breakthrough pain) and transdermal patch are available |
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What substrate is fentanyl have?
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CYP3A4 substrate (DDI)
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What is oxycodone?
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Oxycodone: Orally-active semi synthetic derivative of morphine.
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What is the most widely used opioid
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codeine
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What is codeine?
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moderately potent agonist from opium poppy.
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What are three reasons why codeine is the most used opioid?
What is it commonly formulated with? |
Less euphoria than morphine, lower potential for abuse, rarely produces dependence (at commonly used doses)
Commonly formulated with aspirin or acetaminophen |
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Heroin does what to morphine? Describe its potency compared to morphine?
It leads to the increase of what 3 things compared to morphine? |
Deacetylation of morphine → 3X↑potency vs. morphine.
↑ lipid solubility ↑ access to BBB ↑ euphoria vs. morphine. |
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What does Mixed agonist-antagonist equal?
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Mixed agonist-antagonist = drugs that activate one receptor and block another.
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How do Mixed agonist-antagonist differ from mu-receptor agonists?
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1.Effects depend upon previous exposure to opioids
2.naïve patients→ agonist/analgesia 3.Opioid dependent patients → agonist/antagonist drugs may cause withdrawal symptoms due to antagonist activity |
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what was the goal of development of Opioid Agonists/Antagonists and Partial Agonists
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< respiratory depression and addictive potential.
Clinical use limited by side effects and limited analgesic efficacy. |
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Nalbuphine and butorphanol are what kindof receptors? What do they exert? What do they act as to do this?
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competitive μ-receptor antagonists but exert analgesic actions by acting as agonists at κ receptors.
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Buprenorphine is a ____ _____ at μ receptors?
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Buprenorphine is a partial agonist at μ receptors.
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when is Buprenorphine used?
What are advantages of it compared to methadone? |
Used in opiate detox → less severe and shorter duration withdrawal symptoms vs. methadone
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Pentazocine is what kind of opioid agonist/antagonist?
What can it cause? Used for the tx of what? |
Pentazocine is κ receptor agonist and weak antagonist at μ and δ
Can cause dysphoria and psychosis-like side effects Used for treatment of moderate pain |
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What do opioid antagonists bind with to opioid receptors?
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Opioid antagonists bind with high affinity to opioid receptors
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what 3 components do the Pharmacological effect of opioid antagonists depend upon:
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Whether or not an opioid agonist has been administered
The pharmacological profile of that opioid The degree to which physical dependence upon the opioid has developed |
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During shock or stress, what are activated?
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During shock or stress, endogenous opioid systems are activated and antagonists may have visible consequences
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Naloxone and naltrexone are what kind of receptors?
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competitive opioid receptor antagonists
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What do Opioid antagonists have use in treatment of?
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opioid toxicity
(Rapidly reverse respiratory depression) |
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Naltrexone is FDA approved for treatment of what?
Naloxone is used to treat what? |
alcoholism
opioid overdose |
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What can naloxone decrease when used in a pregnant mother?
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Can be used to ↓ neonatal respiratory depression 2° to opioid consumption by the mother
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what are three signs of Acute Opioid Toxicity
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Coma
Pinpoint pupils Depressed respiration |
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What can antagonists be used to help diagnose?
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help diagnose physical dependence on opioids
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